Oxidation of Tertiary Homoallylic Alcohols by Thallium Trinitrate : Fragmentation vs . Ring Contraction

A oxidação de álcoois homoalílicos terciários com trinitrato de tálio (TTN) foi investigada. Os álcoois que possuem uma metila na posição alílica perdem uma molécula de acetona via uma reação de fragmentação, levando a uma mistura de álcoois alílicos isoméricos como principais produtos, juntamente com os correspondentes derivados acetilados. Por outro lado, o tratamento com TTN de álcoois terciários análogos, sem a metila na posição alílica, fornece indanos, através de uma reação de contração de anel.


Introduction
The reaction of primary homoallylic alcohols with thallium(III) salts has been carefully investigated by several groups, and these studies revealed four main different reaction pathways governed mainly by the structure of the substrate. 1The formation of cyclic ethers through an electrophilic cyclization has been the most explored reaction (Scheme 1, Reaction A). [2][3][4][5][6][7] With homoallylic alcohols bearing an endocyclic double bond, oxidative rearrangement may lead to a ring contraction product (Scheme 1, Reaction B), [6][7][8][9] as exemplified by the preparation of the indan 2 from the alkenol 1 using thallium trinitrate (TTN) (Scheme 2). 9e observed that in these rearrangements the hydroxyl group has an active role, facilitating the addition of the thallium(III) to the double bond.The third type of reaction reported between thallium(III) and 3-alkenols proceeds via fragmentation, in which a molecule of formaldehyde is lost (Scheme 1, Reaction C). 10,11 This reaction was discovered by Kocovský and Baines in the early 90's, resulting in an efficient approach to obtain the hormones estrone and estradiol. 12,13Finally, homoallylic alcohols can afford a diastereomeric mixture of products of addition of the solvent when treated with thallium(III) in the presence of methanol (Scheme 1, Reaction D). 7,9 Although the reactivity of several primary homoallylic alcohols has been investigated, the behavior of the corresponding tertiary alcohols has not been studied.Thus, we decided to investigate the reactivity of a series of tertiary homoallylic alcohols analogous to 1, with Scheme 1. thallium(III).However, as described herein, the oxidation of these substrates with TTN can give either fragmentation or ring contraction products depending on the structure of the substrate.

Results and Discussion
The required tertiary homoallylic alcohols 4a-g were prepared in good yields from the reaction of the esters 3a-g 9 with excess of methyllithium (Table 1). 14reatment of the tertiary homoallylic alcohols 4a-b with TTN, under conditions similar to those used in the ring contraction of 1, failed to form the expected indans.Instead, the isomeric primary allylic alcohols 5a-b and 6a-b were obtained, together with minor amounts of their acetylated derivatives 7a-b and 8a-b.Presumably, a molecule of acetone is lost in these fragmentations (Table 2, entries 1 and 2).
The different reactivity of 4a-b when compared to 1 can be explained considering the mechanism for the thallium(III) mediated ring contraction of homoallylic alcohols.In the rearrangement of 1, the coordination of the thallium(III) with the hydroxyl group leads to the formation of a heterocyclic six-membered ring intermediate.However, we believe that the formation of an analogous intermediate (10) from the substrates 4a-b would be sterically hindered, due to the presence of three methyl groups too close to each other, on which two of them would be in an axial position, as exemplified for 4a in Scheme 3.
The behavior of 4c in the oxidation with TTN is slightly different from 4a-b, because the indan 9c was isolated in addition to the fragmentation products (Table 2, entry 3).The formation of 9c can be rationalized as a result of the thallium(III) mediated oxidative rearrangement of the fragmentation product 5c, which bears a methoxyl group at the para position of the migrating carbon 8a, increasing its migratory aptitude and, thus, facilitating the ring contraction (Scheme 4). 17,18In the analogous allylic alcohols 5a-b this mesomeric effect can not operate.To corroborate this proposition, the reaction of 4c was performed using enough TTN to consume all 5c formed.Indeed, under such a condition, the indan 9c was obtained in 42% yield (Table 2, entry 4).Three possible mechanisms can be invoked for explaining the fragmentation reaction of the alcohols 4ac.First, the mechanism previously proposed by Kocovský and Baines 13 for the thallium(III) promoted fragmentation reactions was applied for the homoallylic alcohol 4a (Scheme 5, path A).The first step is an anti-Markovnikov electrophilic addition of the thallium(III), forming the cyclic ether 11.This step also represents a 5-endo-trig ring closure, which is usually not favored.Reorganization of the bonds would lead to the loss of acetone, affording the allylic carbocation 12, which after solvolysis gives the final products 5a-8a.Considering that the course of several thallium(III) mediated cyclization reactions had been well explained by an initial 4-exo-trig cyclization, which proceeded by a Markovnikov addition of thallium(III), 4 we set out to expand this feature in the Kocovský mechanism through a new sequence of events (Scheme 5, path B).As the thallium(III) is isoeletronic to Pb(IV) and based on the recent work of Preite and Cuellar, 19 the thallium(III) π-allylic complex 16 was postulated as the key intermediate in the third hypothesis (Scheme 5, path C).
Instead of the fragmentation products observed in the oxidation of the alcohols 4a-c, the substrates 4d-g gave the ring contraction products 17d-g when treated with TTN (Table 3).Furthermore, these ring contraction products 17d-g were obtained in higher yields using 1.5 equiv.(59-65%) than using 1.1 equiv. of TTN (37-60%).This can be explained by the fact that the ring contraction is faster when the amount of the oxidizer is increased.Thus, the formation of byproducts is reduced, giving higher isolated yields for 17d-g.In entries 2 and 4, the starting material was not totally consumed, even with 1.5 equiv. of TTN.Thus, the alcohol 4g was treated with 1.7 equivalents of TTN expecting that the yield could be further increased.However, albeit no starting material was recovered, the yield was lower (59%) than that with 1.5 equivalents (65%).We consider that the additional excess of TTN oxidizes the ketone moiety of the indan 17g.The indan 17g was obtained exclusively in the trans configuration, which agrees with a similar result previously described. 9n summary, the reaction with TTN of the tertiary homoallylic alcohols 4a-c, which bear an allylic methyl group, fails to form the expected ring contraction products.a Ratio determined by 1 H NMR. b The geometry of the double bonds in 6a-b, 8a-c was assigned by comparison with the literature. 16nstead, the observed products are those originated from a fragmentation reaction.On the other hand, treating analogous tertiary alcohols without the allylic methyl group (4d-g) with TTN gives the corresponding indans (17d-g), in good yield, through a ring contraction reaction.

Experimental
General THF was freshly distilled from sodium/benzophenone.Other reagents were used as received.Column chromatography was performed using silica gel Acros 200-400 Mesh.TLC analyses were performed with silica gel plates Merck, using p-anisaldehyde solution for visualization. 1 H and 13 C NMR spectra were recorded on Bruker spectrometers.IR spectra were measured on a Perkin-Elmer 1750-FT.Gas chromatography analyses were performed in a HP-6890 series II.High resolution mass spectra were performed on a VG Autospec/Fission Instrument and MicroTOF LC from Bruker Daltonics.

Table 1 .
Preparation of the tertiary alcohols